Vasoactive intestinal peptide (VIP) has a number of biological effects including with respect to hemostasis, the immune system, and the nervous system. See, Delgado et al., The Significance of Vasoactive Intestinal Peptide in Immunomodulation, Pharmacol. Reviews 56 (2):249-290 (2004). For example, VIP has a beneficial effect on blood and pulmonary pressure and on a wide range of immunological and inflammatory conditions. VIP has great potential as an active agent for pulmonary hypertension, chronic obstructive pulmonary disease (COPD), arthritis, inflammatory bowel disease (IBD), and asthma to mention a few.
There are at least two receptors for VIP, including VPAC1 and VPAC2. These receptors bind both VIP and the related molecule pituitary adenylate cyclase-activating polypeptide (PACAP) to some degree. Both receptors are members of the 7-transmembrane G-protein coupled receptor family. VPAC1 is distributed, for example, in the CNS, liver, lung, intestine and T-lymphocytes. VPAC2 is found, for example, in the CNS, pancreas, skeletal muscle, heart, kidney, adipose tissue, testis, and stomach.
The short half-life of VIP renders this peptide impractical as a pharmaceutical agent. See Pozo D, et al., Tuning immune tolerance with vasoactive intestinal peptide: A new therapeutic approach for immune disorders. Peptides 28(9):1833-1846 (2007). Indeed, studies have shown that the half-life of VIP in blood is less than 2 minutes (Domschke et al., 1978, Gut 19: 1049-53; Burhol et al., 1978, Scand J Gastroent 13: 807-813). Further, the multitude of biological effects of VIP may complicate its development for any particular indication. Modified versions of VIP are therefore needed to render the agent therapeutically practical, for example, by extending half-life and/or designing molecules having desirable receptor-binding profiles.